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Targeting molecular signals involved in the development of castration resistant prostate cancer

TARGETING MOLECULAR SIGNALS INVOLVED IN THE DEVELOPMENT
OF CASTRATION RESISTANT PROSTATE CANCER
by
Llana Pootrakul
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
December 2007
Copyright 2007 Llana Pootrakul

A significant clinical problem is that patients who are initially responsive to androgen ablation therapy often develop castration resistant carcinoma of the prostate (CRPC), despite recent advances in cancer therapy. A better understanding of the complex contributing molecular mechanisms underlying the development of CRPC is necessary so that the most appropriate therapeutic targets may be identified. In order to further our understanding of the development of castration resistance, we have established a unique clinical cohort designed to represent successive stages in the development of CRPC. Immunohistochemical analysis (IHC) on clinical specimens allows for identification of potential prognostic markers of prostate cancer, and the use of in vitro cell line models allows for molecular manipulation and assessment of signal transduction events in the progression to CRPC, and will also permit testing of novel rational therapeutics. Our lab has previously identified that overexpression of receptor tyrosine kinase Her-2/neu plays a significant role in castration resistant cell proliferation and survival [Shi 2006]. Recently, involvement of many additional proteins in the development of castration resistance has been suggested, including induction of survival-associated proteins Survivin and Grp78 (78 kDa glucose-regulated protein). Survivin has been shown to promote resistance to antiandrogen treatment in prostate cancer, both in vitro and in vivo [Fortugno 2002, Zhang 2005]. Immunoreactivity of stress response protein Grp78 has been identified as a putative marker of CRPC [Mintz 2003], while preclinical data has validated Grp78 as a functional cell surface molecular target for prostate cancer [Arap 2004].; This study identifies both Grp78 and Survivin as novel survivalassociated markers involved in the development of castration resistant prostate cancer, and directly examines the combined roles of Grp78, Survivin, and Her-2/neu in cell survival during the development of castration resistance. This is accomplished by downregulation of Survivin and/or Grp78 expression through siRNA interference, and blockage of Her-2/neu activity via Herceptin treatment in castration resistant C42B cells. It is the hope that these experiments will provide valuable information as to whether Grp78, Survivin, and Her-2/neu can form a potentially therapeutic combination of targets for the management of CRPC.

TARGETING MOLECULAR SIGNALS INVOLVED IN THE DEVELOPMENT
OF CASTRATION RESISTANT PROSTATE CANCER
by
Llana Pootrakul
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
December 2007
Copyright 2007 Llana Pootrakul